Clinical implications of post-thrombotic syndrome (PTS)

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Clinical implications of

post-thrombotic syndrome (PTS)

Marit Engeseth, MD

Department of Hematology Oslo University Hospital

Oslo, Norway

&

Institute of Clinical Medicine, Faculty of Medicine,

University of Oslo, Oslo, Norway

Oslo, 2022

“Education is not the learning of facts, but the training of the mind to think.” Albert Einstein

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© Marit Engeseth, 2023

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-348-0158-7

reproduced or transmitted, in any form or by any means, without permission.

Cover: UiO.

Print production: Graphics Center, University of Oslo.

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Acknowledgements

“Coming together is the beginning. Keeping together is progress. Working together is success.” Henry Ford

The present work was carried out at the Institute of Clinical Medicine, Faculty of Medicine at University of Oslo and the Department of Hematology, Oslo University Hospital,

Rikshospitalet and Ullevål, during the period January 2016 - january 2021. The work was supported by the South-Eastern Norway Health Autority. I am grateful for all the support that made this project possible.

I want to express my graditute and respect to all the patients that participated in our work, and especially our focus group participants that all generously shared their experiences with PTS to complete strangers around the table. Thank you to my collegues within the South- Eastern Norway Health Autority that took their time to recruit patients to our focus groups, and the doctors and nurses at our outpatient clinic at, Ullevål, making room for me within your tight clinical work schedule.

Main supervisor, Hilde. Thank you for giving me the opportunity, and guidance troughout this project and for the patience when I needed to learn how to conduct qualitative

research. I also thank you deeply for giving me space, maybe some times to much space, but then catching me again when you though it was about time to deliver and conclude. Thank you for your contribution of the data collection, for help with the analyses of the qualitative data, and for your mathematic and statistical skills in the quantitative part of this project.

Thank you for understanding the role of being a researcher and doctor, but most

importantly, also a mother. Your knowledge in venous thromboembolism, contacts within the field and research experience, have been a tremendous help and resourse to me.

Co-supervisor, Tone. The first author of the great CaVenT trial. First, thank you for letting me use all the data you worked years to collect. Your thorough insight into this study population and within the field has been so helpful. Secondly, I wish to thank you for all your help with the data collection and participation in the analyses of the qualitative study. At last, but not at least, I am grateful for your quick responses and english language skills. Always being so well-articulated and to the point in your statements.

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5 Co-supervisor, Per Morten. Thank you for being responsible for the acquisition of external financial support of this project. Thank you for letting us find the path that you already knew on our own. Importantly, asking for results when I was way beyound deadline and keeping me on my toes until I delivered. Thank you for letting us use the CaVenT population in the quantitative part of this project.

Co-author, Marit Helen Andersen. You metholological guidance led me through the conduction of my first qualitative study, and most importantly overseeing the analyzing steps in our qualitative study. Thank you!

To all my colleagues at Forvalterboligen. I have been pendling a lot back and forth, but when I worked from there, I really enjoyed sharing our frustrations, accomplishments, computer problems and birthday celebrations.

Family and friends

My lovly collegues at Ullevål and friends. Thank you for all the love, yellow notes, chocolate surprises and cheering my way. I cannot wait to use more time becoming a better clinical doctor, but most importantly to take better care of my friends. To my three lovely siblings, my hardworking, active, generous, and always supportive parents, my mother- and father-in- law, and the rest of our crazy, big family. Thank you for always being there for me, and for filling my sparetime with no alone time, with heated discussions at long and late dinners. I could not ask for a better familiy.

Ulrik, Herman, and Agnes, your are the meaning of life it self. My biggest accomplisment.

Thank you for just being you and constantly reminding me of what’s most important in this life. I love you forever! Lykke, thank you for your cheers from the dogsite on our couch, and for the forest runs to clear out my head.

My best friend, the love of my life. Successful, hard working, generous, and handsome.

Always cheering me up, and making me stribe to be a better version of my self. Thank you for your english skills, research experience, for repeatedly reading, and correcting my manuscripts. I love you!

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Abbreviations

ACCP = American college of chest physicians CaVenT = Catheter-directed venous thrombolysis CONSORT = Consolidated standards of reporting trials

COREQ = Consolidated criteria for Reporting Qualitative checklist CDT = Catheter-directed thrombolysis

CEAP = Clinical etiological anatomical physiological classification CI = Confidence interval

CUS = Compression ultrasonography CVD = Chronic venous disease DOAC = Direct oral anticoagulants DVT = Deep vein thrombosis

EQ-5D-3L = European quality of life- 5 dimensions - 3 levels ESC = European society of cardiology

ISTH = International society on thrombosis and haemostasis LMWH = Low-molecular-weight heparin

NNT = Number needed to treat PE = Pulmonary embolism PTS = Post-thrombotic syndrome PTP = Pretest probability

QoL = Health-related quality of life RCT = Randomized clinical trial

SPSS = Statistical package for social sciences VCSS = Venous clinical severity score

VEINES = Venous insufficiency epidemiological and economic study VKA = Vitamin K antagonists

VTE = Venous thromboembolism

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Summary

Background

Patients previously affected with a proximal deep vein thrombosis (DVT) have a high and under-communicated morbidity, mainly caused by the long-term complication post- thrombotic syndrome (PTS). There are no laboratory tests, imaging, or functional tests to assess PTS. Various scoring systems have been used to evaluate PTS in clinical trials, resulting in diverging results across different study populations and within the same study population.

Studies acknowledge that the lack of a gold standard for PTS assessment is an important barrier to successful research and improved care for this patient group. The need for a valid and reliable reference standard for diagnosing and grading PTS has inspired the present work.

Aims

1.The overall study objective was to compare the diagnostic accuracy of the Villalta scale, as assessed by healthcare personnel, with PTS diagnosed in line with clinical practice, i.e., in patients with a previous objectively verified DVT no earlier than 3-6 months post-DVT when presenting with characteristic chronic symptoms without any other obvious comorbidity, as a reference standard.

2. In addition, we aimed to identify core symptoms and clinical presentation that might form the basis for a more accurate diagnostic tool for future PTS assessment.

3. Finally, we examined possible predictors of PTS during long-term follow-up of a proximal DVT population where PTS was assessed in line with clinical practice.

Materials and methods

In Paper I, we explored typical PTS complaints through patients' experience and expert opinion with a qualitative approach utilizing interviews of four focus groups. We then related the interview findings to the items of the Villalta scale. In Paper II, we invited 170 still-living patients with a history of proximal DVT during 2006-09 (i.e., participants of the Catheter- directed venous thrombolysis, CaVenT, study) to participate in a one-time visit cross-

sectional follow-up study of long-term complications after DVT. We performed quantitative analyses evaluating the diagnostic accuracy of the Villata scale by comparing the scale items with four predefined mandatory clinical criteria that are in line with PTS diagnosis in clinical

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8 practice (i.e., 1. An objectively verified DVT; 2. Chronic complaints (> 1 month) in the DVT leg; 3. Complaints appeared after the DVT; and 4. An alternative diagnosis was unlikely). In Paper III, we evaluated possible predictors of PTS diagnosed as in clinical practice from variables at baseline and six-months follow-up visits of the CaVenT study.

Results

Paper I: The typical reported PTS complaints included agonizing discomforts, skin changes, fluctuating heaviness or swelling during the day and with activity, and post DVT concerns such as fear of DVT recurrence, health services failing to meet the patients’ expectations, and psychological and social restrictions. We found that PTS patients grade their PTS severity by limitations in physical performance, limitations in social functioning, and the degree of physiological distress following the PTS rather than by the items defined by the Villalta scale.

Paper II: With the predefined clinical criteria as a reference, the sensitivity and specificity of the Villalta scale for diagnosing PTS were 75% (95% CI 60-87%) and 66% (95% CI 50-80%), respectively. Patients with PTS diagnosed by the Villalta scale only more often experienced pain or had comorbidity that could explain their leg symptoms and signs, whereas patients diagnosed by the clinical criteria only had more often fluctuating heaviness and edema.

Paper III: We found that younger age and a higher baseline Villalta score were independent predictors of PTS, i.e., OR 0.96 (95% CI, 0.93-0.99), and 1.23 (95% CI, 1.02-1.49),

respectively.

Conclusions

By examining the diagnostic accuracy of the Villalta scale through a combination of methodologies, our findings indicate that the diagnostic accuracy of the Villalta scale has limitations and does not seem to capture several typical PTS complaints or reflect

adequately on the importance of PTS symptoms and signs. Further, PTS is still a common chronic complication up to ten years following an acute DVT. Both patients and health care professionals should have this in mind when PTS symptoms develop during long-term follow- up of DVT patients. Younger patients with severe symptoms at baseline might have a higher risk of developing PTS, and clinicians should increase their level of attention to this group.

Our findings indicate a strong need for an improved diagnostic approach in PTS assessment.

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Papers in the thesis

This thesis is based on the following papers, referred by their Roman numerals throughout the thesis.

PAPER I

Marit Engeseth, Tone Enden, Marit Helen Andersen, Per Morten Sandset, Hilde Skuterud Wik

Does the Villalta scale capture the essence of post-thrombotic syndrome? A qualitative study of patient experience and expert opinion

J Thromb Haemost. 2019 Oct; 17(10):1707-1714. doi: 10.1111/jth.14557.

PAPER II

Marit Engeseth, Tone Enden, Per Morten Sandset, Hilde Skuterud Wik Limitations of the Villalta scale in diagnosing post-thrombotic syndrome Thromb Res. 2019 Dec; 184:62-66. doi: 10.1016/J.thromres.2019.10.018.

PAPER III

Marit Engeseth, Tone Enden, Per Morten Sandset, Hilde Skuterud Wik

Predictors of long-term post-thrombotic syndrome following high proximal deep vein thrombosis: a cross-sectional study

Thromb J. 2021 Jan 8; 19(1):3. doi: 10.1186/s12959-020-00253-8.

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1. Introduction

“The presence of an introduction is held to imply that there is something of consequence and importance to be introduced.” Arthur Machen

1.1 Pathophysiology, epidemiology, and risk factors of venous thromboembolism

1.1.1 Definition of venous thromboembolism

Venous thromboembolism (VTE) is a condition where abnormal blood clotting leads to the formation of a blood clot within a vein. Most commonly the clots form in the deep veins of the lower extremities. Sometimes a deep vein thrombosis (DVT) breaks free, and the embolus travels with the venous circulation towards the heart and when finally lodging within the pulmonary arterial circulation causing a pulmonary embolism (PE) (1-3).

Throughout the years, a growing amount of research has added to the evidence that PE and DVT are two entities of the same disease, thus the term VTE (3, 4). A DVT of the lower limb is usually classified as proximal or distal (Figure 1). Proximal DVTs are located in the

iliofemoral and the popliteal vein (3, 5), and distal DVTs are located in the infra-popliteal veins (Figure 1) (6).

Figure 1. Deep venous system of the lower extremity. With permission from Elsevier (7).

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11 1.1.2 Epidemiology of venous thromboembolism

VTE is the third most common cardiovascular disease after myocardial infarction and stroke (8-10). The incidence of DVT has been constant over time, but the reported incidence of PE is increasing. The latter is proposed due to the use of more sensitive imaging techniques

diagnosing patients with PE under hospital admission (11). VTE is a common disease

associated with substantial morbidity, mortality, and a high recurrence rate (12, 13). VTE is a significant health problem among men and women (14), has increasing incidence with older age, and has the highest incidence in Caucasians and African Americans (15). In addition, there is a transitory higher incidence of VTE among women during childbearing age (4, 16, 17). The annual rate of VTE is 0.7-1.4 per 1000 person-years (8, 9, 11, 18), and in Norway, the yearly incidence of VTE is 8000 -10.000 (8).

1.1.3 Pathophysiology of venous thromboembolism

About two centuries ago, the German physician Rudolph Virchow described three causative factors explaining a hypercoagulable state that precedents a thromboembolic event (2, 19):

First, stasis can be caused by either obstruction or immobilization. Secondly, the presence of a hypercoagulable state. Finally, an injured or dysfunctional vascular wall prevents inhibition of coagulation. In combination, these factors induce hypercoagulability by activating the coagulation cascade (4, 18).

1.1.4 Risk factors of venous thromboembolism

VTE is a multifactorial disease, and the etiology of the condition involves acquired (modifiable or non-modifiable) risk factors and inherited interacting predispositions of thrombosis, as summarized in Table 1.

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12 Table 1. Risk factors for developing venous thromboembolism*

Acquired risk factors

Previous venous thromboembolism Hospitalization for heart or atrial fibrillation (< 3 months)

Surgery** Myocardial infarction (<3 months)

Major trauma*** Chronic liver disease

Pelvic, and lower limb fractures Superficial vein thrombosis Congestive heart failure or respiratory failure Varicose veins

Infection*^v Catheterization

Active cancer^v Long distance travel

Obesity (BMI >30) Pregnancy and puerperium

Age (especially >70 years) Oral contraception

Nephrotic syndrome Hormone replacing therapy

Antiphospholipid antibodies Myeloproliferative disorders

Smoking Corticosteroid use

Lower limb paralysis Inflammatory bowel disease flare Inherited risk factors

1^st degree relative with a previous venous thromboembolism May-Thurner syndrome

Thrombophilia

* Adapted from (3, 10, 16, 20)

**Major surgical procedures (neurosurgical, hip or knee replacement, spinal, and major abdominal operations)

***Spinal cord injury

*^v Urinary tract, pneumonia, HIV

v Hematological malignancies, pancreatic cancer, gastric cancer, and brain cancer.

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1.2 Diagnostics, treatment, and prevention of deep vein thrombosis

1.2.1 Diagnostics of deep vein thrombosis

Diagnostic assessment of DVT is performed in sequential steps. The pretest probability (PTP) is initially assessed by clinical decision rules for DVT, e.g., the Wells score (4, 18, 21). D- dimer, a molecular marker developed from the dissolution of cross-linked fibrin often elevated in thrombotic conditions (18) is then measured. A negative D-dimer has an

essential role in ruling out DVT because of its high sensitivity (4). However, the specificity of the D-dimer is low as it is also elevated in non-thrombotic conditions, e.g., pregnancy, traumas, infections, cancer, and high age (11, 18, 21). The recent incorporation of age- adjusted D-dimer cut-off values may improve the performance of D-dimer testing with increasing age (10). Patients with a low PTP and a negative D-dimer are considered unlikely to have a DVT and do not need to proceed to diagnostic imaging (4, 11). Compression ultrasound (CUS) for proximal DVTs has a specificity of approximately 95% and a sensitivity of > 90% (10, 18). In patients with a high PTP of a DVT and a negative CUS, a repeated CUS after one week is recommended (21). Diagnostic imaging of DVT with angiography, CT, or MRI can objectively verify the presence of venous thrombus. These techniques can be a supplement in individual patients but is not a part of current clinical practice and the sequential diagnostic work-up.

1.2.2 Treatment of deep vein thrombosis

At the end of the 17th century, etiological theories such as "congestion of evil humors" and

"undigested breast milk in the lower limb" gave rationale to preventing and treating DVT by bloodletting or breastfeeding. In 1793, Hunter hypothesized that a DVT resulted from blood clots within the vein. Surgical ligation of the vein, in addition to strict bed rest with iron bars attached to their patients' lower limbs, became the treatment of choice to prevent

thrombus migration (2, 22).

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14 Figure 2. Early treatment of deep vein thrombosis; devices to favor strict immobilization.

With permission from John Wiley & Sons- Books (22)

Since the early 1920s, DVTs have been treated with anticoagulants (22). DVT treatment consists of three phases: The initial weeks, long-term (i.e., 3-6 months), and extended treatment (i.e., beyond 3-6 months) (4, 11). The initial treatment goals are the prevention of DVT extension, thrombus migration to the lung circulation, and hemodynamic collapse and death. The treatment goal of the long-term and extended phases is to prevent recurrent VTE (4).

There has been a change in the recommended anticoagulation therapy for treating VTE during the last decade. The 2016 American College of Chest Physicians (ACCP) guidelines and the 2014 and 2017 European Society of Cardiology (ESC) guidelines recommend direct oral anticoagulants (DOACs) for treating both DVT and hemodynamically stable PE (11).

Prior to the development of DOACs, anticoagulation with Vitamin K antagonists (VKAs) was the standard oral treatment for VTE for more than 50 years (10, 22). Although VKAs are safe and reliable when used correctly, clinicians and patients must take several precautions to ensure correct use. During the initial days of VKA treatment, patients are still in a

thrombogenic state. Thus, therapeutic doses of subcutaneous Low-Molecular-Weight Heparin (LMWH) must be administered for a minimum of five days until International Normalized Ratio (INR) has been in the therapeutic range, i.e., 2.0-3.0 for ≥ 2 days. Other

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15 disadvantages of VKA treatment are the need for continuous INR monitoring, a narrow therapeutic range, and multiple interactions with other drugs and dietaries (23).

The DOACs include the direct thrombin inhibitors and factor Xa inhibitors (11). The DOACs have several advantages over VKAs, including rapid onset, fixed doses, no need for

monitoring of the anticoagulation effect, no known interactions with dietaries, and minimal interactions with other drugs (10, 23). However, VKAs are still regularly used to treat VTE in selected cases (11).

1.2.3 Prevention of deep vein thrombosis

In Europe, approximately 500.000 people die each year due to VTE, which is more than twice the combined deaths from AIDS, breast cancer, prostatic cancer, and traffic accidents (13).

Approximately 60 % of patients diagnosed with VTE are hospitalized or in nursing home confinements (20, 24). Ten percent of sudden deaths among hospitalized patients are due to PE, and 75% of the cases affect patients admitted with non-surgical conditions (25). Since approximately one-third to a half of the DVTs are idiopathic, DVT prevention can be

challenging in the general population. Among high-risk patients (Table 1), both mechanical prophylactic treatment with elastic compression stockings (ECS), avoiding dehydration, and preventive use of anticoagulants are used for DVT prevention (4).

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1.3 Post-thrombotic syndrome

In 1271, the first known DVT case was described in Gaillaume de Saint Pathus

manuscript: “La vie et les miracles de Saint Lois” where the 20-year-old Raol suffers from unilateral leg pain and swelling. The surgeon recommended to "wait and see," which resulted in the development of a lower leg ulcer likely to represent severe post-thrombotic syndrome (PTS) (22).

PTS is the most common long-term chronic complication after a DVT (26), and patients with a previous DVT have a high-, and under-communicated morbidity caused by PTS (27, 28). Up to 50 % of the patients with a high proximal DVT develop PTS (26, 29, 30). PTS patients experience reduced health-related quality of life (QoL) and represent considerable costs to society (despite being otherwise healthy) (31-33).

1.3.1 Clinical characteristics of post-thrombotic syndrome

PTS is defined as a syndrome because it manifests with a spectrum of intermittent or persistent symptoms and signs (Table 2) (34). Hence, there is both intra- and interpatient variation in the clinical presentation of PTS. PTS complaints are typically aggravated in the supine position and decreased by elevation of the affected limb. The complaints worsen during the day and are relieved overnight (34, 35). Manifestations of PTS vary from mild symptoms and signs to more severe cases, such as painful venous ulcers and venous claudication. Venous claudication results from persistent venous obstruction resulting in bursting leg pain during increased working demand (36, 37).

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17 Table 2. Clinical characteristics of PTS*

Symptoms Clinical signs

Pain Edema

Discomfort from swelling Telangiectasia

Cramps Venous ectasia

Heaviness Varicose veins

Fatigue Redness

Itching Cyanosis

Pruritus Hyperpigmentation

Paresthesia Eczema

Bursting pain Pain during calf compression

Venous claudication Lipodematosclerosis

Atrophie blanche Open or healed ulcers

* Adapted from Kahn et al. (38)

1.3.2 Pathophysiology of post-thrombotic syndrome

A persistent thrombus and incomplete recanalization of the vein causes venous outflow obstruction (38). In addition, direct damage through the volume effect of a thrombus or indirect damage by secondary inflammatory processes, cause venous valvular damage and venous valvular reflux (39, 40). Venous outflow obstruction and venous valve reflux can both lead to venous hypertension. Ambulatory venous hypertension is suggested to represent the major pathophysiological mechanism leading to the clinical manifestations consistent with PTS (36, 38, 41, 42).

Furthermore, studies have reported possible associations between PTS and inflammatory markers such as D-dimer, factor VIII/XI/XIII, C-reactive protein, P-selectin, plasminogen activator inhibitor-1, interleukin-6, and intracellular adhesion molecule-1. These

inflammatory markers are associated with impaired fibrinolysis leading to delayed thrombus removal, induction of vein wall fibrosis, and eventually a non-compliant vein wall (39, 43).

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18 Persistent venous hypertension reduces calf muscle perfusion, and this leads to a

dysfunctional microcirculation with increased tissue permeability, eventually presenting as edema, subcutaneous fibrosis, and in severe cases, ulcerations (40, 42).

1.3.3 Diagnostics of post-thrombotic syndrome

There is no objective, functional, or laboratory diagnostic test for PTS (44). In clinical practice, patients with a previously objectively verified DVT are diagnosed with PTS when presenting with typical symptoms, and clinical signs, no earlier than 3 - 6 months after the index DVT, without any other obvious comorbidity in the affected limb (35).

Different approaches have been used in clinical trials to define PTS because of the lack of a gold standard diagnostic test (45); the strategies have typically included assessment of 1.

Venous hemodynamic status, 2. Clinical status, 3. QoL questionnaires.

1.3.3.1 Venous hemodynamic status

Compression ultrasound assessment of the deep veins of the lower limb can verify the presence of residual vein thrombus (RVT) by examining the vein compressibility combined with doppler for the evaluation of venous flow and valvular reflux (46, 47). Air

plethysmography (APG) measures venous outflow fraction for the evaluation of any persistent venous outflow obstruction (47).

1.3.3.2 Clinical status

Several clinical tools have been developed for PTS assessment in clinical trials. These clinical tools include the Villalta scale (Table 3) (45), the Ginsberg measure (Table 3) (48), the Brandjes scale (49), the Widmer scale (50), the Clinical, Etiological, Anatomical, and Physiological classification (CEAP) (51), and the Venous Clinical Severity Score (VCSS)(52).

The Villalta scale, the Ginsberg measure, and the Brandjes scale are developed explicitly for PTS assessment, and the others are developed for chronic venous disease (CVD) assessment (50, 53).

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19 1.3.3.2.1 The Villalta scale

The Villalta scale was developed in 1994 and introduced in an abstract to both diagnose and gradethe severity of PTS (54). A cross-sectional study of 100 patients evaluated at 6 and 36 months following a venography-verified DVT provided the data that validated the scale (55).

During the Villalta scale development process, a physician not involved in evaluating the ratings of the individual components of the scale assessed how venous symptoms and signs interfered with the patients ’daily life. Using the degree of interference with daily life as a reference, the researchers suggested cut-off points for PTS and PTS severity (55).

In 2009, the International Society of Thrombosis and Haemostasis (ISTH) recommended using the Villalta scale for diagnosing, grading, and follow-up of PTS in clinical trials to standardize the assessment of PTS for research purposes (45) (Table 3).

Table 3. Scorings systems evolved for PTS assessment in clinical trials

The Villalta scale (45)*/** The Ginsberg measure (48)**

Symptoms (scored by the patient)

Typical pain and swelling—worse by standing/walking and relieved by rest/

elevation of the leg ≥ 1 month duration and

≥ 6 months after the DVT.

o Pain o Cramps o Heaviness o Paresthesia o Itching Clinical signs

(scored by caregiver, nurse/physician) o Pretibial edema

o Skin induration o Hyperpigmentation o Redness

o Venous ectasia

o Pain on calf compression

*The Villalta scale: Each item is rated on a four point severity scale ( zero = none, three = severe). A total score of ≥ 5 points corresponds to any grade of PTS; 5-9 points mild PTS, 10-14 points moderate PTS, and ≥15 points or the presence of a venous ulcer to severe PTS. A score <5 indicates no PTS (45).

** The Ginsberg measure does not grade PTS, the Villalta scale also assess severity grade of PTS.

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20 The Villalta scale was recommended as it is reported to be reproducible and sensitive to clinical changes, to provide a good interrater agreement (55, 56), to be acceptable for users, and it includes a severity grading (57). The Villalta scale is now widely accepted and used in cohort studies and in recent multicenter randomized clinical trials evaluating functional endpoints (30, 58-61). A visual guide was published in 2009 to further standardize the grading of the clinical signs (45). In 2016, a patient reported Villalta scale was published where the patients themselves scored all 11 symptoms and clinical signs from the Villalta scale with the help of an explanatory text and a visual guide to make patient follow-up in clinical trials easier (62).

1.3.3.3 Health-related quality of life questionnaires

Evaluation of subjective patient outcomes and assessment of perceived illness burden in clinical trials can be performed through standardized and validated generic and disease- specific QoL questionnaires. Several studies have reported associations between PTS severity and generic and disease-specific QoL (63-65). The disease-specific QoL questionnaire VEINES QoL/Sym assesses venous disease-specific QoL and venous symptom severity (65, 66). This questionnaire contains 26 items regarding problems of the lower limbs, i.e., symptoms, limitations in daily activity, and psychological impact over the last four weeks, and changes during the last year. VEINES QoL summary score assesses QoL, and VEINES-Sym score measures symptom severity only. For the VEINES-QoL and the VEINES-Sym scores, higher values reflect better QoL or fewer symptoms, respectively (65).

1.3.4 Risk factors of post-thrombotic syndrome

Researchers have focused on identifying clinical and biomarker predictors with an effort to find patients at high risk of developing PTS for prognostication and individualized

information, and follow-up after the DVT (44, 67). Of the most acknowledged risk factors for the development of PTS are high proximal DVT and recurrent ipsilateral DVT (67). Additional factors associated with PTS development are summarized in Table 4. The first PTS prediction models have been published, and the total scores for each model can be calculated based upon different clinical characteristics (68-70). Rabinovich et al. found that proximal DVT, DVT located in the iliac vein, body mass index (BMI) ≥ 35 kg/m², and moderate to severe Villalta category at baseline, together predicted a higher risk of PTS development (68). Amin et al.

predict PTS development by characteristics in the acute phase or in the subacute phase (i.e.,

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21 6 months): Age > 56, BMI > 30, female sex, varicose veins, history of venous thrombosis, smoking, proximal location of the thrombus and if the thrombus was provoked (69). Mean et al. report PTS prediction based on age ≥ 75 years, prior varicose vein surgery, multi-level thrombosis, concomitant antiplatelet/non-steroidal anti-inflammatory drug therapy and the number of leg symptoms and signs (up to 11) (70). The prediction model by Rabinovich is based on PTS diagnosed by the Ginsberg measure 6 months or more after the index DVT.

Additionally, this prediction was developed as a part of the SOX trial (58) where patients with recurrent DVT were excluded (71). The prediction rules developed by Mean and the one developed by Amin are based up on PTS diagnosed by the Villalta scale. However, the

prediction models differ as Mean diagnosed PTS at 24 months and excluded patients < 65 years, whereas Amin assessed PTS by the Villalta scale after 6 months and involved a younger population (69, 70).

Table 4. Risk factors for post-thrombotic syndrome*

Non-modifiable risk factors

Extensive proximal DVT (26, 36, 68, 72)

Severe symptoms at diagnosis of DVT (68, 73, 74) Older age (26, 75)

Preexisting venous insufficiency (72, 74, 76, 77)

Persistent venous signs/symptoms one month after the acute DVT (26) High D-dimer (43)

Modifiable risk factors

Obesity (BMI > 30kg/m²) (72, 76, 78) Recurrent ipsilateral DVT (68, 79, 80)

Residual thrombus on ultrasound 6 months after the DVT (46, 47) Quality of initial (oral) anticoagulation (38, 80)

*Adapted from (44, 68, 81)

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22 1.3.5 Prevention of post-thrombotic syndrome

The best way to prevent PTS is obviously to avoid developing a DVT. Thus, pharmaco- therapeutic, and mechanical thrombosis prophylaxis in high-risk patients and high-risk settings are currently the most effective measures to prevent PTS (25, 44). In addition, treating obesity by lifestyle intervention or surgery, and reducing recurrent ipsilateral DVT and residual thrombosis by adequate anticoagulation may also reduce PTS risk (Table 4). In a recent large cohort study, Prandoni et al. found a significant lower incidence of PTS in

patients with a prior proximal DVT treated with DOACs versus heparin and VKAs (82).

1.3.5.1 Elastic compression stockings

The effect of elastic compression stocking (ECS) for PTS prevention is controversial (29, 49, 71). Recent randomized clinical trials (RCTs) have examined the efficiency of ECS for PTS prevention. However, neither two years of daily use, individualized duration, or custom- made ECS have resulted in a significant prophylactic effect against PTS development (61, 83).

Consequently, guidelines no longer recommend ECS for PTS prevention (71).

1.3.5.2 Early thrombus removal techniques

Early thrombus removal techniques involve systemic thrombolysis, catheter-directed thrombolysis (CDT), and pharmaco-mechanical catheter directed thrombolysis (PCDT) (71).

The introduction of CDT for PTS prevention was based upon the “open vein hypothesis”: An accelerated removal of the thrombus would save delicate valves from inflammatory

destruction and more rapidly restore venous functioning and thus, preventing the

pathophysiological mechanisms of PTS development from persistent venous hypertension (47). During the years 2006-09 our research group conducted a multi-center randomized intervention study with 20 participating hospitals in the South-Eastern health region of Norway. The study is known as the Catheter-directed Venous Thrombolysis (CaVenT) study.

The CaVenT study group randomized 209 participants with a first-time upper femoral and/or iliofemoral DVT to receive additional CDT or conventional anticoagulant treatment with LMWH followed by warfarin. The primary endpoint was the difference in PTS prevalence after two years assessed by the Villalta scale. 41.1% of the patients allocated to additional CDT developed PTS compared to 55.6% in the control group (p=0.047). The difference corresponded to an absolute risk reduction of 14.4%, and the number needed to treat (NNT) was 7. This benchmark study was published in The Lancet in 2012 and received substantial

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23 international attention (30). The five-year follow-up data were available in 176 out of the initially included 209 CaVenT participants, and the long-term results of this study showed sustained and additional benefits of CDT. Thirty-seven (43%) of the patients allocated to the CDT group had developed PTS as assessed by the Villalta scale compared to 63 (71 %) in the control group, corresponding to an absolute risk reduction of 28 % and an NNT of 4 (84). In the recent ATTRACT and the DUTCH CAVA studies, both open label RCT on PCDT, no

preventive effect with PCDT was detected when using the Villalta scale for PTS assessment (30, 59, 83). Thus, CDT is currently confined to patients with severe symptomatic iliofemoral DVT (e.g., massively swollen, to the point of limiting ambulation) or with phlegmasia cerulea dolens (i.e., with the effort to save the lower limb and not for PTS prevention) (71).

1.3.6 Treatment of post-thrombotic syndrome

No curative treatment for PTS has been identified (38). However, several compression therapies have been used to relieve PTS complaints and improve functioning. If tolerated, daily use of knee-high ECS, with compression classes ranging from 20-30 mmHg to 40-50 mmHg, is recommended for patients with established PTS (85). In patients with symptoms not adequately controlled with ECS, an intermittent battery-driven compression device may be tried (38). Venoactive drugs such as rutosides, defibrotide, and hidrosmin to treat chronic venous symptoms have been tested for PTS treatment. However, their effects have been examined in only a few smaller studies and are still unknown (38, 71). Additionally, there is no studies showing efficiency of diuretic towards PTS related edema (85). Lifestyle

interventions with physical exercise programs have been tried, and improving calf muscle functioning, calf muscles strength, leg flexibility, and overall fitness may exert a positive effect on PTS complaints (86, 87). Increased venous return is promoted by avoiding a sedentary lifestyle, elevating the affected limb whenever possible, avoiding long heat exposure, and reduce weight (i.e., BMI < 30). That mentioned, these are only

recommendations as no robust evidence of effect exist up to this date (71). Interventions such as endovascular treatment (EVT) and surgical correction of central vein occlusions or infrainguinal venous valve incompetence are confined to patients with severe symptomatic PTS when conservative treatment fails after an individual evaluation (38, 85, 88). A

multicenter RCT is ongoing on the effect of EVT in patients with disabling iliac-obstructive PTS (C-TRACT trial NCT03250247).

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24

1.4 A gold standard diagnostic test for PTS is missing

“In the absence of the gold standard, there is no way to protect savings from confiscation through inflation. There is no safe store of value.” Alan Greenspan

So far, the presence of venous abnormalities found by objective measurements, or other diagnostic imaging modalities after a DVT, has not been consistent with the clinical

characteristics of PTS (57, 89). Therefore, different clinical tools have been used to diagnose PTS in studies (90). Unfortunately, low correlation between the clinical tools have limited the comparability of results across studies, and further problems with implementing study findings into clinical practice and patient care (83, 90, 91). It is proposed that including QoL when assessing PTS in addition to clinical measurements would be superior to an assessment of PTS by clinical symptoms and signs alone, as this approach would add valuable

information about the burden of illness (50, 92). The validity of the recommended Villalta scale was originally established by demonstrating a correlation with relevant health outcomes, e.g., generic and disease-specific QoL (57), and recognized anatomic or physiologic correlates of PTS (46, 93). Therefore, one could argue that the reason for the strong correlation between the VEINES QoL/Sym questionnaire and the Villalta scale is that the same symptoms and clinical signs are assessed in both clinical tools as some studies has shown association with disease-specific Qol, but not generic QoL questionnaires (32, 94).

Thus, in the absence of an objective measurement of PTS the validity of the various clinical tools is associated with uncertainty.

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1.5 Study rationale

“Education is for improving the lives of others and for leaving your community and world better than you found it.” Marian Wright Edelman

Several studies on VTE have influenced the treatment of acute and recurring VTE, and the management of bleeding complications from anticoagulant treatment (35, 95). Still, up to 2006 very few clinical trials on VTE involved PTS as a primary endpoint (22, 41).

About 30% of VTE patients will experience recurrent VTE within 10 years (4). A well- established risk factor for PTS is recurrent ipsilateral DVT (26, 38, 96). In the absence of curative PTS-treatment, and even as approximately one third to a half of all DVTs are idiopathic, early prediction of individuals at high-risk for developing PTS will be beneficial (68).

As PTS develops gradually over years, and without effective approaches for the prevention and treatment, patients may be met with a lack of knowledge and understanding from health care providers (92, 97). This may be explained by limited knowledge in the general medical community about PTS, in combination with little success in incorporating study findings into clinical practice because of diverging results across clinical trials on PTS (30, 45, 58-60).

Over the years, our research group has made extensive contributions to the field of venous thrombosis including basic research, translation research, epidemiology, and clinical randomized controlled trials. A number of these studies have focused on long-term complications after DVT. Accordingly, the researchers in our group have become increasingly aware and concerned about the limitations in the diagnostic accuracy, i.e., specificity and sensitivity, of the Villalta scale when studying patients previously affected with a DVT. We have experienced that patients with chronic leg problems, such as an obvious sequela from a previous ankle fracture, arthritis, edema due to heart failure, or primary chronic venous disease (CVD) (6, 38, 98-101) have their complaints labelled as related to PTS when entered into the Villalta scale at study visits. Such false positive entries will reduce the specificity of the Villalta scale.

Similarly, we have encountered patients with leg problems that obviously relate to previous thrombosis, i.e., they have appeared in the index leg after a DVT, and there is no other

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26 comorbidity, who have leg complaints that are not recognized as PTS-related by the Villalta scale. This is most typical for patients suffering from venous claudication. With vigorous exercise these patients have limited physical performance from severe pain and tightness in the index limb because of a persistent obstruction of venous flow. These symptoms typically subside with rest (36). Since the Villalta scale does not assess activity related symptoms these patients’ symptoms may fail to qualify as PTS-related according to the Villalta scale. Such false negative entries will reduce the sensitivity of the Villalta scale.

Venous symptoms and signs of PTS may resemble the subsiding symptoms from an acute DVT as these may persist for months before they eventually resolve (38, 45). As a result, in clinical practice PTS is diagnosed when patients with a prior DVT presents with characteristic chronic symptoms with no other obvious comorbidity in the affected limb no earlier than 3 - 6 months post-DVT (38, 45, 71). In contrast to clinical practice, the Villalta scale does not reflect on the duration of the symptoms and signs (i.e., chronicity), or whether they have appeared or worsened following the DVT. Additionally, the Villalta scale fails to distinguish between healed and open ulcers, the latter a sign of severe PTS (92).

In summary, in our opinion there is a need to improve the clinical diagnosis and grading of PTS. This will be of benefit for future clinical PTS studies on pathophysiology, predictors, prophylaxis, and treatment. More reliable and valid results of future studies could eventually improve health care to patients with PTS with positive effects for both patients and their families, and significantly reduce their need of health care services and welfare support.

Thus, the initiation of the present work was inspired by an increasing awareness and concern about the lack of a valid and reliable reference method for diagnosing and grading of PTS and the implications on both research and clinical practice.

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2. Aims of the thesis

“The great aim of education is not knowledge but action.” Herbert Spencer

PAPER I

The aim of paper I was from a first-person perspective to search for an understanding of which complaints and concerns patients with obvious post-thrombotic symptoms and signs experience through a qualitative approach. The study focused on the patients` experiences of chronic leg problems after DVT, the associated burden, the importance of the different symptoms and signs, and the impact on their health related QoL and daily living. Finally, we aimed to relate this to the items of the Villalta scale.

PAPER II

The aim of Paper II was to examine the diagnostic accuracy of the Villalta scale by using PTS assessment in line with clinical practice as reference in patients with a history of upper femoral and/or iliac DVT. The sensitivity and specificity of both the Villalta scale and the Ginsberg measure were assessed with four mandatory and predefined clinical criteria as reference.

PAPER III

The aim of paper III was to study both previously known and possible new predictors of PTS in patients with long-term PTS following an upper femoral and/or iliac DVT when PTS was defined and assessed by the four mandatory and predefined clinical criteria in line with clinical practice as reference.

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3. Materials and methods

“Plans are worthless, but planning is everything.” Dwight D. Eisenhower

3.1 Study design

This project was conducted as a combination of qualitative and quantitative methodology, so-called mixed method research (102). A widely accepted definition of mixed methods research, is research that focuses on collecting, analyzing, and mixing both quantitative and qualitative data. Mixed method research can be in a single study or a series of studies (103).

Our study design was sequential, i.e., the qualitative study was followed by two quantitative studies, and accordingly, our mixed method study design is quantitative dominant.

3.2 Study population

In 2016, we invited health care workers, i.e., clinical experts, and patients considered to present with clinically relevant PTS (i.e., had sought health care because of their leg problems after DVT), to participate in a qualitative study with focus group interviews. The first focus group consisted of five clinical experts highly experienced in working with patients with a history of DVT (i.e., senior consultants in circulation physiology, hematology,

radiology, and vascular surgery, plus one thrombosis nurse). Sixteen patients were recruited from either outpatient clinics within the South-Eastern Norway Regional Health Authority, or among participants from previous studies on long-term outcomes after DVT. Of these, five participants were from the CaVenT study. Six of the patients were recruited by senior

consultants at Oslo University Hospital participating in the clinical expert focus group. All the participants in our qualitative study, paper I, were selected through a purposive sampling approach likely to provide us with rich and thorough information relevant to the research question (104, 105). For paper II and III we invited in 2017, the 170 patients still alive from the CaVenT study to participate in a one-time visit, cross-sectional follow-up study. All 88 (52%) who agreed to participate in the study were included (Figure 3).

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29 Figure 3. Study population in the quantitative part included from the CaVenT study, adapted from Enden et al. (30) and Haig et al. (84).

3.3 Data collection

3.3.1. Focus group interviews

The interviews took place in a seminar room without interference from outside and lasted for approximately two hours. We audio recorded all the interviews so they could be

transcribed verbatim by Marit Engeseth immediately after they were conducted. In addition, we had field notes that summarized important non-verbal communication. Marit Engeseth conducted the interviews, and Tone R. Enden and Hilde S. Wik served as moderators and facilitated the discussions within the groups to make sure that everyone could speak if they wanted. Each participant was given the opportunity to talk to the researchers alone

immediately after the focus group interviews. The clinical experts were interviewed in a focus group prior to the three patient focus groups. Qualitative studies do not have a predefined sample size but stop the inclusion when new participants no longer rise themes not already addressed by previous participants, i.e., when the point of saturation is reached (104, 106).

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30 The focus groups started by welcoming the participants and introducing the interviewer and the moderator, followed by an information about the background and the aim of the study, and why they were selected as participants. An oral explanation of anonymity,

confidentiality, and the right to discontinue their participation at any time were given, followed by the possibility to ask questions. We informed that the oral communication would be audio recorded, and that this would be handled confidentially and used for the declared purposes only. We had a flexible interview guide to ensure that similar questions were phrased in an open-ended manner in each group (Table 5). A flexible interview guide allowed us to revise the interview guide during the data collection process by incorporating new themes that were introduced in the previous focus group to explore these issues within the following focus groups (Table 5).

Table 5. Flexible interview guide

1. Use three minutes to write down keywords describing your complaints (patients)/how you experience PTS-patients` complaints (clinical experts)

2. Questions (open-ended with time for discussion)

a. How long after the DVT did your complaints appear? When did you have the DVT?

b. Have your complaints changed over time? Increased, decreased?

c. How would you characterize your complaints?

d. At what time of the day are your complaints worst?

e. In what situations do your complaints appear?

f. Do you have visible signs of PTS?

g. Do your complaints affect your functioning?

h. Is there anything that decreases your complaints?

i. Have you been in contact with healthcare workers because of your complaints?

3. Summary by the investigator. If we have understood you correctly…etc. Something you want to add? Travel expenses you want us to compensate?

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31 3.3.2 Self-reported outcomes

In both study populations, the patients were asked to report the following outcomes:

1. If they considered themselves to have PTS (PTS not present, mild PTS, moderate PTS, or severe PTS). 2. Self-reported level of function due to PTS (not reduced because of PTS, mildly reduced because of PTS, moderately reduced because of PTS, or severely reduced because of PTS). Finally; 3. Self-reported quality of life due to PTS (not reduced because of PTS, mildly reduced because of PTS, moderately reduced because of PTS, or severely reduced because of PTS).

In the quantitative part of the project, the patients met for a one-time study visit at the outpatient clinic, Department of Hematology, Oslo University Hospital, Norway. In the first part of the study-visit the patients completed the self-reported outcome forms and

questionnaires on both health-related generic (107-109), and disease-specific quality of life (QoL) (65, 66). We made sure the patients were not disturbed and did not receive any help when completing the forms.

A study specific clinical report form (CRF), including findings from the qualitative project, was made especially for this part of the project and included: Specific characteristics of possible leg symptoms and signs, i.e., specific characteristics of possible discomforts, if the symptoms and signs had diurnal changes, if they affected their physical activity level appearing with increased workload and were relieved at rest, if the complaints differed with the positions of the leg or with different temperatures. Further, possible skin changes were explored and if present, the degree they had influenced each patient was noted. They were also asked if the prior DVT had influenced their contact with the health care system. Further, we scrutinized issues of the lower leg carefully to evaluate possible comorbidities. If lower leg comorbidity were found, the chronology of the lower leg symptoms and signs in the previous affected limb, i.e., index DVT, were explored in addition to the chronicity of these complaints.

Eventually the patients were also asked about their occupation, the use of ECS,

anticoagulants, smoking status and weight. PTS was also assessed by using the Ginsberg measure. The CRF was completed during the study visit with the study investigator Marit Engeseth.

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32 The study visit ended with a full clinical evaluation of the lower limbs including the

assessment of PTS by the Villalta scale (Table 3), and by the four mandatory predefined clinical criteria in the index DVT limb (Table 6). The study visits lasted for approximately 1.5 hours and were scheduled between 8 am and 4 pm on working days. All patients were instructed not to wear their ECS upon arrival on the day of the study visit.

3.3.3 Questionnaires

3.3.3.1 Assessment of post-thrombotic syndrome

In both study populations PTS was assessed by the Villalta scale (Table 3). The six symptoms were scored by the patients, and the clinical signs were assessed by Marit Engeseth using the Villalta visual guide developed by Kahn et al. (45).

In the CaVenT population, PTS in the index DVT leg was assessed by the Ginsberg measure (Table 3) (48), and by four mandatory and predefined clinical criteria in line with how PTS is diagnosed in clinical practice (Table 6) in addition to the Villalta scale (Table 3). Both lower limbs were examined clinically, and characteristics of the patients’ leg symptoms and signs and various leg comorbidities, including varicose veins, previous surgery, fractures, and musculoskeletal disorders were registered. If comorbidity was present, we addressed at what time the symptoms and signs in the index limb had appeared and related them to the timing of the index DVT, as well as the chronicity of the patient’s complaints, were further explored.

Table 6. PTS reference standard in line with PTS assessment in clinical practice Four mandatory and predefined clinical criteria for PTS

1. Previous objectively verified DVT

2. Development of chronic complaints in the DVT leg

3. The complaints appeared or worsened following the DVT

4. An alternative diagnosis to the patient’s complaints is not likely

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33 3.3.3.2 Assessment of generic health-related quality of life

When assessing QoL in clinical trials it is recommended to use both a generic-, and a disease- specific questionnaire (63, 66). Generic instruments are constructed to report on general concepts around QoL and can be used in patients with different diseases and in different populations. For generic QoL assessment we used the Norwegian version of the EuroQol five-dimensional three-level version (EQ-5D-3L) questionnaire. EQ-5D-3L is a standardized, and widely used instrument to assess generic QoL (108, 109). EQ-5D-3L consists of a descriptive system of QoL (states) including five dimensions: mobility, self-care, activity, pain, and anxiety, each of which can be scored according to three levels of severity (’no problems’, ’moderate problems’, and ’severe problems’) reflecting the patients’ health status that day (107). The results of the EQ-5D-3L health states may be converted into a single number, an index value, meaning a weighted mean of the five dimensions as a health state with a value ranging from -0.59 (health worse than death), 0 (dead) to 1 (best possible health) (108-110).

3.3.3.3 Assessment of disease-specific health-related quality of life

A disease-specific QoL questionnaire assesses QoL by focusing on details on possible impaired QoL due to a specific condition. The disease-specific QoL questionnaire VEINES-QoL/SYM is frequently used when studying DVT populations. It is not specific for DVT but developed for CVD in general. The VEINES-QoL/sym was translated into Norwegian and validated in in 2009 (65). In the CaVenT study population disease-specific QoL was assessed using the Norwegian version of the VEINES-QoL/Sym questionnaire (65, 66). The VEINES-QoL/Sym assesses disease- specific QoL and symptom severity; it consists of 26 items covering the last 4 weeks, and whether these have changed during the last year. For the two summary scores VEINES-QoL and the VEINES-Sym, higher values reflect better QoL or fewer symptoms, respectively (65).

3.3.4 Data from the CaVenT study

We extracted data from baseline, six months, and two- and five-years follow-up of the CaVenT study. Baseline variables included: Age, gender, comorbidity, allocated treatment arm within the CaVenT study, smoking, and duration of symptoms before the DVT diagnosis.

The localization of the baseline DVT were categorized as isolated pelvic, iliofemoral, or upper femoral DVT based on routine diagnostic imaging. Further, D-dimer, C-reactive protein (CRP), Villalta score, and increased calf circumference measured in centimeters at the level of the

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34 tuberosity of the tibia between the index leg and the contralateral leg. DVT was categorized as provoked if occurring following trauma, immobilization, or surgery, and in patients with cancer, hormone-replacement therapy (HRT), or recent pregnancy.

For the predictor analysis in paper III, a baseline variable “DVT with pelvic involvement” was made that included both iliofemoral and isolated pelvic DVT. Further we registered if

patients had D-dimer ≥ 0.5 μg/mL and CRP ≥ 4mg/L (i.e., baseline values above the reference level in Norway at the time of the study; 2006 - 09). Possible predictors from the six months follow-up data included femoropopliteal reflux, i.e., venous incompetence with reflux defined as venous valve closure time > 0.5 m/sec on duplex ultrasound, and iliofemoral patency, i.e., flow in the pelvic and femoral vein with complete compressibility of the femoral vein and no functional venous obstructions, as assessed by ultrasound and air plethysmography, respectively (47). Finally, we included the variables daily use of ECS, and recurrent ipsilateral DVT, from two- and five-years follow-up.

3.4 Data analysis

3.4.1 Qualitative part of the project, paper I

“If we knew what we were doing, it would not be called research, would it?” Albert Einstein The interviews were analyzed using Kvaale & Brinkman’s method for thematic analysis. We performed an inductive analysis process to generate meanings from the raw data to identify patterns and themes (111). First, the transcribed interviews underwent multiple readings to get an overall impression of the data. Second, the participants’ responses were identified, labeled, and divided into units of meaning. Third, all responses were read, and themes dominating the units of meaning were stated as clearly as possible. Fourth, we analyzed the units of meaning regarding the specific purpose of our study; exploring the typical patients’

experience of living with PTS and relating these findings to the Villalta scale. In the fifth, and final step, the most important themes, i.e., the main domains with related categories, were incorporated into a descriptive statement. Hilde S. Wik, Tone R. Enden, and Marit Engeseth reviewed the data analyses to ensure that the results captured all primary data and selected quotations that best illustrated our findings with an effort to make the interpretations clear, credible, and transferable.

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35 3.4.2 Quantitative part of the project, paper II and III

“Do not worry about your difficulties in Mathematics. I can assure you mine are still greater.”

Albert Einstein

For all the statistical analysis in the quantitative part, paper II and III, we used the Statistical Package for Social Sciences (SPSS) version 25 (SPSS Inc, Chicago, Illinois, USA). We presented the normally distributed continuous variables as means and standard deviations. A two- sample t-test was used for comparison between groups. Continuous variables that were not normally distributed, were presented as medians and interquartile ranges, and a non- parametric test (Mann–Whitney) was used for comparison between groups. All statistical tests were two-sided. P -values < 0.05 were considered statistically significant.

3.4.2.1 Data analysis Paper II

Sensitivity and specificity of the Villalta scale and the Ginsberg measure (Table 3) were calculated with PTS diagnosed by the four mandatory and predefined clinical criteria as a reference (Table 6). The EQ-5D-3L summary index was calculated based on values from a Danish population (107). The VEINES-QoL and VEINES-Sym scores were computed using standard scoring algorithms obtained from the authors (66).

3.4.2.2 Predictor analysis Paper III

The continuous variables age, Villalta score at baseline, differences in leg circumference, and duration of symptoms before DVT diagnosis were presented as mean with standard deviation (SD). The dichotomous variables gender, daily smoking, DVT with pelvic vein involvement, left sided DVT, additional CDT, and daily use of ECS were presented as frequencies with percentages. By using bivariate logistic regression, we tested if previously reported associated factors for PTS development (additional CDT treatment, differences in leg circumference, lack of iliofemoral patency, and presence of iliofemoral reflux), were differently distributed between patients with and without PTS. We did not dichotomize the continuous variables as they were kept in their original form within the analyses. The Wald test was used to test the level of significance. Further, within the multivariate logistic regression model, we included all variables with P-values < 0.20 from the bivariate analyses. We conducted the multivariate logistic regression model with backward variable selection, until all the remaining variables were statistically significant. The results from the bivariate and multivariate logistic regression

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36 were presented as odds ratios (OR) with 95% confidence intervals (CI). The significant variables in the final model were checked for possible interactions.

3.5 Ethical considerations

Our study protocol, the semi- structured interview guide, and the written informed consents were all approved by the Regional Committee for Medical and Health Research Ethics (REK), No. 2015/1567D. The studies were performed in accordance with the revised Helsinki Declaration. No harm was anticipated among the study population as our studies were observational, and no intervention was performed. All participants were given verbal and written information about the aim and design of the study. They were assured the right to discontinue their participation at any time and that the collected data would be handled in a confidential way. Prior to each focus group interview all participants were ensured

confidentiality and anonymity in both verbal and written from. Further, if they considered something to be too delicate to share within the group, they were offered to share this only with the interviewer and moderator after the focus group interview. They were all informed that their responses would not affect their treatment. To maintain anonymity and

confidentiality in paper I research results are presented in a way so that the participants are not recognizable. Throughout the entire process, all collected data were coded and

anonymized. The audio recorder and code list were stored in a locked storage at Oslo University Hospital only available for the primary investigator Marit Engeseth. All invited participants that accepted to participate in both studies were included, and no one withdrew from the studies.

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Clinical implications of post-thrombotic syndrome (PTS)